Schizophrenia is a common, devastating illness, which most often leads to life long disability. Greater understanding of schizophrenia's pathophysiology might lead to novel medications with improved safety and efficacy. Dendritic spines are the chief site of excitatory neurotransmission in the neocortex and their reduction on deep layer III pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia might contribute to the cognitive deficits observed in the illness. In this K08 Mentored Clinical Scientist Award, the candidate will test the general hypothesis that a reduction of dendritic spines in the DLPFC of subjects with schizophrenia might be associated with alterations in the mRNA and protein expression of PTPRF, AGTR2, IGF1R, MARCKS, PPP1R9A, and ARHGEF2. These 6 genes regulate dendritic spines and preliminary data suggests their mRNA expression is altered in schizophrenia. While investigating these hypotheses, the candidate, a general psychiatrist, will undertake a program of study in 1) 3-D reconstructions of neurons and their processes, Western Blots, and duallabel immunofluorescent microscopy, 2) the use of Quantitative Real-Time PCR (QRT-PCR) and in situ hybridization, 3) the molecular mechanisms which regulate dendritic spines and contribute to their loss in schizophrenia, 4) advanced statistical methods as they apply to neuroanatomical and gene expression data;and 5) relevant areas of neuroscience as they apply to the pathophysiology of schizophrenia. Acquiring these skills under the mentorship of Professors Francine M. Benes, and Joseph T. Coyle will enable the candidate to launch an independent career investigating the pathophysiology of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a devastating chronic disease affecting 1% of the population worldwide, and despite recent advances in treatment, schizophrenia often produces life-long disability. The goal of the proposed experiments is to better understand the molecular and cellular alterations associated with the illness with the hope that molecular targets will be identified for novel medications having improved efficacy and safety.